This project has the long-term objective of improving our understanding of the pathogenesis of idiopathic hypercalciuria and nephrolithiasis in man by studying genetic hypercalciuria and nephrolithiasis in the rat. We have successfully bred a colony of genetic idiopathic hypercalciuric (IH) stone forming rats, now in their 31st generation, whose daily urinary calcium excretion (UCa) is 8 to 9 times greater than controls. The mechanism of the increased UCa appears to be increased intestinal Ca absorption in addition to a smaller component of renal Ca leak and/or enhanced bone resorption. The female IH rats have greater urinary supersaturation with respect to brushite (CaHPO4) and have a greater kidney Ca content than either normocalciuric females or males or IH males. After eating standard rat chow for 4 months, 12 of 19 female and 5 of 5 male IH rats had renal and/or ureteral calcifications and many of these had hydronephrosis. There was no calcification or hydronephrosis in any of 10 controls. These IH rats appear to be an excellent model of human idiopathic hypercalciuria; however with the IH rat we are able to precisely regulate dietary ionic constituents to a degree not possible in humans and thus are able to critically control the extent and duration of urinary ion excretion and thus supersaturation with respect to individual ionic complexes. We propose to test the following hypotheses: 1) That stone formation and nephrocalcinosis in the IH rat is a function of urinary supersaturation and time by determining a) the degree and type of urinary saturation and time necessary for stone formation, b) the independent role of gender in stone formation, c) the independent role of citrate in stone formation and d) the role of thiazides, furosemide and acetazolamide in altering supersaturation and stone formation in IH rats. 2) That differences in crystallization inhibitors Tamm-Horsfall protein and/or nephrocalcin explain why only some IH rats form stones despite equivalent supersaturation for similar periods of time by a) comparison of inhibitor activity in normocalciuric control and IH rats, b) comparing the inhibitor activity in IH rats that do and do not form stones and c) determining the effect of alterations of magnitude and type of urinary supersaturation on inhibitor activity. 3) That bone from IH rats has a greater sensitivity to 1,25(OH)2D3 but not to other calcitropic agents compared to bone from control rats by a) culturing isolated neonatal rat calvariae from control and IH rats with and without 1,25(OH)2D3, and other calcitropic agents to measure basal and stimulated bone resorption b) comparing basal and stimulated osteoclastic and osteoblastic activity in bones from control and IH rats. 4) That there is abnormal in vivo regulation of serum 1,25(OH)2D3 in IH rats by determining the dynamic regulation of serum 1,25(OH)2D3 ionized Ca serum phosphorus and PTH.